Focal Segmental Glomerulosclerosis (FSGS) is a major cause of chronic kidney disease in childhood. This glomerulopaty is more frequent in minority populations, and often recurs in the transplanted kidney. Despite advances particulary in molecular genetics, the cause and optimal treatment of this condition remains poorly defined. Uncontrolled studies in adults with FSGS support the use of prolonged prednisone therapy. Preliminary data in children suggests that the calcineurin inhibitor tacrolimus may be efficacious in patients who have been refractory to other therapies. The purpose of this multicenter study is to compare the relative efficacy of tacrolimus with that of intensive prednisone therapy in preventing the progression of primary FSGS. This represents the first controlled evaluation of these two promising therapies in children with FSGS. We are proposing a randomized, open-label clinical trial in patients with nephrotic range proteinuria who fail to respond to 4 weeks of oral prednisone and who are found to have FSGS on renal biopsy. Patients will be assigned to receive daily prednisone (60 mg/m2) for 3 months followed by either alternate day prednisone (40 mg/m2) for the ensuing 15 months or tacrolimus plus low-dose alternate day (10 mg/m2) for 18 months. In addition, patients will receive optimal doses of losartan and atorvostatin to control proteinuria, hypertension, and hypelipidemia. The primary outcome indicators will be: complete or partial remission of proteinuria, preservation of glomerular filtration rate, and prevention of renal scarring. Secondary outcome indicators will include correlation of response with a novel histopathologic classification, assessed by a centrol core pathology group. The study design will incorporate collection and storage of potentially important biological samples at the direction of the Data Coordinating Center and the Steering Committee of the NIDDK. The Eastern Regional Group for the Study of Focal Segmental Glomerulosclerosis in Children will be comprised of 41 sites under the direction of the Regional Coordinating Center at Montefiore Medical Center of the Albert Einstein College of Medicine. This project is expected to: 1) improve the outcome of children with FSGS, and, 2) create a nationwide network of clinical investigators that will facilitate future basic and clinical research in the field of pediatric nephrology, in general, and FSGS, in particular.